tbuckley/cabot-search huggingface dataset:
Clinical features, genomic landscapes, and survival outcomes of HER2-low breast cancer.
Authors: Jin Juan, Bin Li, Biyun Wang, Zhonghua Tao, Xichun Hu
Journal: Journal of Clinical Oncology (2023)

1027 Background: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates prompt the identification of the HER2-low subtype. To investigate whether HER2-low breast cancer can be defined as a distinct biological subtype, our study conducted a comprehensive analysis on the clinical and molecular features among patients with different HER2 statuses. Methods: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database. Genomic data of breast tumor samples was generated by targeted NGS using a cancer-related gene panel. The cohort included 220 HER2-zero, 194 HER2-low and 165 HER2-positive patients according to the HER2 status from the most recent pathological results. Results: First, the clinicopathological characteristics of HER2-low patients were associated with hormone receptor (HR) status. Less lymph node invasion and higher bone metastasis in HER2-low patients were probably because of the higher percentage of HR-positive tumors in HER2-low patients than HER2-zero and HER2-positive patients (63.19%, 42.02% and 28.00%, respectively, p&lt;0.0001). Second, HER2 status shifting from primary to recurrent breast cancer was common, with 38.1% and 48.4% of HER2-zero primary tumors converting to HER2-low tumors when they metastasized in the whole population and the HR-positive subgroup, respectively. Third, HER2-low patients had more brain and lung metastases and cases of de novo stage IV breast cancer than HER2-zero patients in the HR-positive subgroup. Fourth, germline BRCA2 mutations were observed only in HER2-low patients (11/139, 7.91%) and HER2-low tumors had more somatic PIK3CA mutations than HER2-zero tumors in the HR-negative subgroup. Fifth, HER2-low patients had a longer median overall survival (mOS) and median disease-free survival (mDFS) than HER2-zero patients (mOS:49.1 vs. 30.3 months, log rank P = 0.0005; mDFS: 28.17 vs. 20.27 months, log rank P =0.036), but difference was not evident when paired by HR status. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, and Cluster 2, which enriched in TP53 mutations, was significantly associated with worse outcomes, which provided novel insights into heterogeneity in HER2-low breast cancer. Conclusions: The clinical and molecular significance of HER2-low status was influenced by HR expression, and HER2-low tumors had distinct features in subtype analyses based on HR status. Our elaboration of molecular subtypes in HER2-low tumors encourages clinicians to consider the heterogeneity in HER2-low breast cancer.
FLEX, a real-world evidence full transcriptome study of 30,000 patients with early-stage breast cancer.
Authors: Eric Allen Brown, Linsey P. Gold, Carl R. Gray, Douglas Kanter Marks, Vibha Taneja Thomas, Alfredo A. Santillan, Ciera S Singleton, M. William William Audeh
Journal: Journal of Clinical Oncology (2023)

TPS621 Background: Clinical trials have been an invaluable tool in providing improvements in the discovery, treatment, and quality of life for various diseases and disorders including breast cancer, which impacts millions of people each year. Historically, patient trial populations have not been racially diverse due to several factors such as bias, healthcare distrust, access, and eligibility criteria. However, current efforts are focused on improving diversity and inclusion to promote efficacy and health equity across all races/ethnicities. The ongoing, multi-center FLEX trial (NCT03053193), which pairs clinical data and full transcriptome expression data, seeks to enroll 30,000 patients to accelerate real world research. Due to the size of the database, it is also expected to capture patients typically underrepresented in clinical trials. Methods: FLEX is the first of its kind, prospective, observational trial that enrolls patients who are ≥ 18 years old with histologically proven stage I-III breast cancer with up to 3 positive lymph nodes. Patient eligibility for study enrollment include standard of care MammaPrint testing with or without BluePrint and consent to clinically annotated full transcriptome data collection. The study infrastructure facilitates the generation of hypotheses for targeted sub-studies. The FLEX network fosters collaboration with 114 sites, including one site in Greece and Israel, encouraging participating investigators to initiate sub-studies that can address research questions that are important for breast cancer management. All proposed sub-studies are vetted and approved by Research and Scientific Review Committees. Since launching in April 2017, 12,569 patients have been enrolled including those who have been historically underrepresented in trials (African American n= 1025; Latin n= 341; Asian n=156). Forty-two investigator initiated sub-studies have been approved and are in progress, with 40 abstracts accepted in national and international congresses. Five ongoing sub-studies within FLEX address differences in underlying biology and treatment response/management among African American, Latina, and Asian American patients with early-stage breast cancer. These studies provide a broader understanding of how differential gene expression patterns unique to racial/ethnic groups can impact treatment outcomes. With the large FLEX database, enrollment and sub-studies are extended to other racial/ethnic groups that are underrepresented in clinical trials, but not limited to specific groups. Overall, the FLEX study strives to use full transcriptome data to improve precision medicine in early-stage breast cancer. Clinical trial information: NCT03053193 .
Association of accelerated approval (AA) status with National Comprehensive Cancer Network (NCCN) guideline recommendation for cancer drug indications: A cross-sectional study.
Authors: Edward Robert Scheffer Cliff, Rachel S Rome, Aaron S Kesselheim, Benjamin N Rome
Journal: Journal of Clinical Oncology (2023)

1599 Background: Many oncology drugs are approved via FDA’s accelerated approval pathway based on trials showing changes to surrogate measures only ‘reasonably likely’ to predict clinical benefit. Despite this preliminary evidence, accelerated approval drugs are incorporated into clinical practice and included in guidelines. We assessed NCCN evidence and preference ratings for drugs with accelerated vs traditional approval. Methods: Accelerated approval oncology drugs were identified using an FDA list as of June 30 2022. Drug labelling revealed other oncology indications of these drugs. Accelerated approvals were stratified if they had been converted to traditional approval after confirmatory studies or withdrawn. Indications with no NCCN guidelines or tumor-agnostic approvals were excluded. Relevant NCCN guidelines were reviewed as of Oct 19 2022. Each indication was assessed for ratings of level of evidence and treatment preference. Levels of evidence included category 1 (consensus, high-level evidence), 2A (consensus, lower-level evidence), 2B (lower-level evidence without consensus), or 3 (major disagreement). Treatment preference rankings included preferred, alternative preferred, other recommended, or useful in certain circumstances. Results: Among 315 indications for 100 drugs, 156 (50%) had traditional approval and 159 (50%) had current or previous accelerated approval. Among accelerated approval indications, 78 (49%) had been converted to traditional approval and 21 (13%) withdrawn. Among all indications, 105 (33%) were rated as category 1 evidence, 185 (59%) as 2A, 6 (2%) as 2B, and 2 (0.6%) as 3. The treatment preference for 153 (49%) was preferred, for 55 (17%) was recommended, for 5 (2%) was alternative preferred, and for 38 (12%) was useful in certain circumstances. Compared to traditional approval, accelerated approval indications less often had category 1 evidence (3% v 47%), and were less often listed as preferred (40% v 58%). Converted accelerated approval indications had mid-range ratings for evidence (38% category 1) and treatment preference (47% preferred). 11 withdrawn accelerated approval indications remained in NCCN guidelines. Conclusions: In most cases, NCCN guidelines identified accelerated approval indications as having lower evidence than traditionally approved cancer drugs. Many traditional approvals and conversions from accelerated approvals had only category 2A evidence, suggesting better evidence is needed for traditional approval of oncology drugs. But in about half of accelerated approval indications withdrawn by the drug’s manufacturer, NCCN continued recommending the drug. Professional organizations like NCCN should ensure their guidelines reflect that accelerated approval drugs are being marketed based on preliminary evidence.
Factors associated with oncotype and recurrence among a diverse breast cancer population seeking care at an urban safety-net hospital.
Authors: Judy Jiaqi Wang, Brendin Beaulieu-Jones, Jose Acevedo, Lauren Oshry, Andrea Merrill, Ariel Hirsch, Michael Ryan Cassidy, Naomi Yu Ko
Journal: Journal of Clinical Oncology (2023)

e12537 Background: The landmark trials, TAILORx and RxPONDER have established Oncotype DX (ODX) as a prognostic and predictive tool in the management of estrogen receptor positive (ER+), early-stage breast cancer. However, recent studies have revealed existing racial disparities in the ODX test. These findings call into question whether ODX is generalizable to diverse populations. We evaluated the prognostic value of ODX RS at an urban, academic safety net hospital. Methods: We conducted a single-institution retrospective study of patients diagnosed with invasive breast cancer and had an ODX test performed between January 1, 2010 to December 31, 2021. Demographic, tumor and treatment characteristics were obtained. Chi-square and ANOVA were used to examine associated factors among recurrences and non-recurrences. Results: We identified 315 patients diagnosed with ER+ breast cancer with an ODX test obtained. Racial breakdown was 47% White, 35% Black and 18% Other. 69% of the patients had public or no insurance. 20% of the patients had a low RS (0-10), 62% had intermediate (11-25) and 18% were high (26-100). 264 patients had no evidence of recurrence, 15 patients had a local or distant recurrence and 36 were unknown. Recurrence was significantly associated with younger age (p = 0.04), higher histologic grade (P &lt; 0.001, &lt; 0.001), intermediate oncotype score (p = 0.002) and no receipt of chemotherapy (p = 0.014). Focused analysis of the recurrence cohort demonstrates a significant proportion with an Intermediate ODX RS classification (93.3%, P = 0.001). 53% had distant recurrence, 20% had received adjuvant chemotherapy and 93.3% were adherent to hormonal therapy. Conclusions: In a diverse patient population, recurrences were significantly more likely among younger patients with high grade tumors, intermediate RS and those who did not receive chemotherapy. Further investigation and understanding whether Oncotype DX is generalizable to diverse breast cancer patient populations is needed.
Virtual nutrition services in oncology.
Authors: Carolyn Lammersfeld, Kara Sonntag, Sadie Dahlk, Nathan Schober, Kayla Morgiewicz, Digant Gupta, Maurie Markman
Journal: Journal of Clinical Oncology (2023)

e13504 Background: In 2016, the National Academy of Sciences, Engineering and Medicine convened a workshop to examine challenges patients experience accessing specialized nutrition care in outpatient cancer treatment settings. Inadequate Registered Dietitian Nutritionist (RDN) staffing and reimbursement were identified as barriers to timely care. Staffing challenges at our three destination community cancer centers led to a backlogged queue of nutrition consults resulting in a ≥ 4-week wait time for an appointment. A quality improvement project to address delays in care for patients at risk for malnutrition, resulted in implementation of a hybrid model utilizing remote RDNs to provide virtual Medical Nutrition Therapy (MNT) to supplement onsite RDNs. Methods: After approved in June 2022, two remote RDNs were hired to provide virtual patient care. Nationwide recruitment allowed for hiring rare talent. A project team was created to assure we followed all regulatory guidelines related to licensing and billing. RDNs were individually licensed in 14 states to cover where ≥ 70% of our patients reside. System-wide criteria and licensure alerts for appointments were established between scheduling and nutrition leaders. The first patients were seen virtually on October 14, 2022, with units of service (uos) logged in 15-minute increments. Results: Appointments were tracked from October 14, 2022, through February 3, 2023. 69.2% of 302 scheduled appointments were successfully delivered virtually via telehealth platform with a mean of 1.7 uos. The main reasons for nonuse of the platform were no shows (52.7%) and the need to convert to a phone call (32.3%). The mean uos was significantly higher in new patients compared to returning patients (2.23 versus 1.53; p&lt;0.001). Conclusions: A hybrid model of onsite and virtual care RDNs has potential to improve access to nutrition care. New patient appointments averaged &gt; 30 minutes, and follow-ups averaged &lt; 30 minutes. This may help inform future scheduling of virtual MNT appointments. This model may allow for recruitment from a wider pool of RDNs. It may also help avoid delays in care for patients at risk for malnutrition and gaps in their cancer treatment. [Table: see text]
Inhibition of FASN as a potential treatment of advanced endocrine therapy-resistant breast cancer.
Authors: Avani Gunuganti, Henriette Balinda, Andrew J. Brenner
Journal: Journal of Clinical Oncology (2023)

e13077 Background: The past decade has seen significant advancement in increasing survival estrogen receptor alpha (ERα) positive breast cancer. The use of selective estrogen receptor down-regulators and modulators (SERMs) and cyclin-dependent kinase inhibitors aided to extend overall survival of breast cancer patients. However, resistance to endocrine therapy is a common occurrence and patients will eventually succumb to their disease. Fatty acid synthase (FASN), a key enzyme in lipid biosynthesis, is overexpressed in more aggressive and therapy-resistant tumors, including breast cancers. FASN inhibitor, TVB-2640, has been evaluated in multiple tumor cell lines and in a phase 1 clinical study, and showed partial responses in 5 patients and multiple patients with prolonged stable disease (≥16 weeks). Methods: We generated therapy-resistant cells by long term exposure to tamoxifen (MCF7/TamR cells), and fulvestrant (MCF7/FR cells). Palbociclib-resistant (MCF7/RB1Crispr and ZR75/RB1Crispr) cells were generated through CRISPR/Cas9 knockout of the retinoblastoma (RB) gene. We assessed the impact of TVB-3166 inhibitor in these cells on proliferation, viability, cell cycle, apoptosis, ERα expression in patient derived explants, and tumor growth in xenografts. RNA sequencing of tamoxifen- and fulvestrant-resistant cells was performed to investigate gene expression. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by western blot after treatment with TVB with or without the addition of palmitate or BAPTA. Results: TVB treatment leads to a marked inhibition of proliferation in tamoxifen-, fulvestrant- and palbociclib-resistant cells compared to the parental cells. RNA sequencing of explants of patients with ERα positive disease showed down regulation of ESR1 related genes and genes involved in invasiveness. RNA sequencing of fulvestrant-resistant cells showed that treatment with TVB results in down regulation of EMT and E2F target genes, cholesterol homeostasis genes and mTORC1 signaling. Additionally, TVB significantly inhibited tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB treatment is mediated through the induction of endoplasmic reticulum stress. Conclusions: Our preclinical data provide evidence that FASN inhibition presents a promising therapeutic strategy for treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine resistant breast cancer should be considered.
Shugoshin as a key mediator in the metastasis of triple negative breast cancer.
Authors: Valeria Julia Hernandez, Shirley Jusino, Yainyrette Rivera Rivera, Camille Chardon Colon, Patrcia C. Rodriguez Rodriguez, Janeishly Roman Gonzalez, Angel Isidro, Harold I. Saavedra
Journal: Journal of Clinical Oncology (2023)

e13098 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen, progesterone, or human epidermal growth factor 2 (HER2) receptor expression. TNBC has poor prognosis due to its high metastatic potential and limited treatment options. Shugoshin-1 (Sgo1), a centromeric protein that maintains stability in chromatids during mitosis, has been thought to play an important role in the progression of TNBC. Previous publications from our group have shown that the transient downregulation of Sgo1 in TNBC cells decrease the epithelial-to-mesenchymal transition (EMT), which is a precursor of metastasis. Our purpose with this study is to evaluate the role of long-term effects of Sgo1 downregulation in cell invasion, cell migration, tumor growth, and metastasis. Methods: To achieve our goal, MDA-MB-231 cells were stably transfected with a lentivirus containing a shRNA Sgo1 sequence or a scramble shRNA control. Cell invasion and migration were evaluated by Boyden chamber assays. Meanwhile, tumor growth and metastasis were evaluated using an immunocompromised orthotopic mice model. Female NOD-SCID Gamma (NSG) mice were injected either with 2.5 X 10 6 shRNA Control (n= 10) or shRNA Sgo1 (n= 10) MDA-MB-231 cells. Tumor growth was measured for eight weeks using a vernier caliper. Afterwards, primary, and metastatic tumors as well as primary organs were harvested. Lung and liver samples were embedded in paraffin and stained with hematoxylin and eosin. A Student t test was used to evaluate the differences between groups. A p-value &lt; 0.05 was considered significant. Results: Our results show a significant reduction in cell invasion and migration in MDA-MB-231 cells treated with shRNA Sgo1. Moreover, we observed a significant reduction in tumor growth and metastasis to lymph nodes, liver, and lungs in the mice treated with shRNA Sgo1 when compared to shRNA Control group. Conclusions: These results suggest that Sgo1 is an important regulator in TNBC tumor growth and metastasis through the modulation of EMT genes. Thus, targeting Sgo1 early in the course of TNBC can be a potential therapeutic treatment of TNBC.
Implementation of a multi-cancer early detection (MCED) test using a centralized model within (w/i) a multi-state health system.
Authors: Gautum Agarwal, Jay W. Carlson, Damon R. Broyles
Journal: Journal of Clinical Oncology (2023)

1526 Background: Cancer is the second leading cause of death globally. Currently, USPSTF recommends screening for only 5 (breast, cervical, colorectal, lung [high-risk], prostate [individualized basis]) cancers, but ~70% of cancer-related deaths are from cancers without recommended screening. Galleri (GRAIL, LLC, Menlo Park, CA), an MCED test, that uses a cell-free DNA-based targeted methylation assay and machine learning classifiers to detect a shared cancer signal and predict the cancer signal origin is available for use as a complement to existing screening tests. We present a model of centralized MCED test implementation w/i a multi-state health system. Methods: From 11/2021-7/2022, clinical and operational leadership w/i the Mercy Health System (headquartered in St. Louis, MO), including 44 acute and specialty hospitals with over 4000 integrated providers and 44000 coworkers in 5 states (MO, KS, AR, OK, IL), created an MCED test implementation plan for their health system. Results: A model with centralized navigation was developed such that patients (pts) and providers contacted a singular team (MCED team) w/i the Mercy Precision Medicine Division using telemedicine to order an MCED test and navigate processes. In the 2 months prior to and after launch (7/12/2022), 12 medical education sessions were held for various groups w/i the health system, including the centralized MCED team, leaders of subspeciality departments, and all primary care providers, to inform on the MCED test implementation plan. In this model, access to MCED testing commences in 2 ways: (1) pts register through an online form or (2) providers w/i the health system submit a referral to the MCED team through the electronic medical record system. Pts are then contacted by a nurse practitioner on the MCED team for pretest counseling w/i 2 business days. If the pt is still interested after counseling, an MCED test is ordered. Pts go to 1 of 11 Mercy labs to have their blood drawn for MCED testing. “Cancer signal detected (CSD)” test results are given to a specialized navigator who helps schedule diagnostic testing and initial appointments with specialists and coordinates follow-up care and treatment (tx) w/i the health system. Early analytics show that from launch to 1/31/2023, there were 3777 total referrals (2931 pt, 846 provider) that led to 925 MCED test orders, of which 6 had a CSD result. Median time from a CSD test result to pt notification was 22.8 hours, to initial diagnostic evaluation was 3.1 days, and to a cancer diagnosis was 8.7 days. Median time from cancer diagnosis to initiation of tx or first postdiagnosis specialist visit was 33 days. Conclusions: This model allowed for efficient time to diagnosis and tx or triage of eligible-risk pts using an MCED test and is an example of how a healthcare system can incorporate and scale the implementation of the MCED test into clinical practice.